Page 160 - Fluorescence-guided cancer surgery

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Chapter 10
where it is expressed primarily at the apical membrane of polarized epithelial cells, including fallopian tube and endometrial tissue16;19;20. Thus, when targeted with a uorescent agent, background uorescence will be low in healthy tissue, making this protein an ideal candidate target for uorescence-guided ovarian cancer surgery. Importantly, because chemotherapy does not a ect the expression of FRα, this protein can be targeted in both primary and interval cytoreductive surgical procedures21;22.
The potential of using a folate analog coupled to a dye that uoresces outside of the NIR spectrum (e.g., folate-FITC) was demonstrated previously in a small patient series, yielding a positive uorescence signal in three out of four patients with ovarian cancer23. Although this study showed the feasibility of detecting uorescently labeled tumor deposits in real time, the approach did not allow the surgeon to detect lesions beneath the tissue surface. In addition, we found that using folate-FITC in both ovarian cancer and breast cancer produces high auto uorescence in healthy tissue (data not shown). This nding underscores the need for agents that uoresce in the NIR spectrum.
OTL38 is a folate analog conjugated to a NIR uorescent dye (excitation at 776 nm, emission at 796 nm); OTL38 has high speci city and a nity for FRα. Here, we rst examined the tolerability, pharmacokinetics, and tissue and blood distribution of increasing doses of OTL38 in healthy volunteers. Based upon these results, we then determined the optimal dosage range and the imaging time window. We then used these parameters in a study in patients with epithelial ovarian cancer in order to determine the correlation between uorescence detection and histopathology of the resected lesions. We also determined whether the detection of tumors using the traditional surgical view was improved with the addition of uorescence imaging.
MATERIALS AND METHODS
Study design
The primary objective of the study in healthy volunteers was to assess the tolerability and pharmacokinetics (in plasma and skin) of a single intravenous doses of OTL38; in addition, the results were used to determine the optimal dosage range and time window for performing intraoperative imaging in the subsequent study in patients with ovarian cancer. For the patient study, the